Error message

No crossref credentials set for molbiolcell

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

Mol. Biol. Cell, 1 June 2007
Vol. 18, Issue 6, p. 2013-2025
DOI: 10.1091/mbc.E06-04-0348

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

  1. Michaël Perrais*,
  2. Xiao Chen*,
  3. Mirna Perez-Moreno§, and
  4. Barry M. Gumbiner*
  1. *Department of Cell Biology, University of Virginia, Charlottesville, VA 22908-0732;
  2. Institut National de la Santé et de la Recherche Médicale, U837, 59045 Lille, France;
  3. Université Lille 2, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Jean-Pierre Aubert Research Center, 59045 Lille, France; and
  4. §The Rockefeller University, New York, NY 10021
  1. Jean Schwarzbauer, Monitoring Editor
  • Submitted April 24, 2006.
  • Revised March 6, 2007.
  • Accepted March 20, 2007.

Abstract

E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to β-catenin is required for cell growth inhibition, but β-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor β-catenin binding to α-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a β-catenin–dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a β-catenin–dependent mechanism that inhibits selective signaling functions of growth factor receptors.

Footnotes

  • Abbreviations used:

    BrdU
    5-bromodeoxyuridine
    EGF
    epidermal growth factor
    EGFR
    epidermal growth factor receptor
    ERK
    extracellular signal-regulated kinase
    Fc-hE
    Fc-hE–cadherin
    FL
    full length
    LEF
    leukocyte enhancer factor
    siRNA
    small interfering RNA
    STAT
    signal transducers and activators of transcription
    TCF
    T cell factor.
  • Citation:

    M. Perrais, X. Chen, M. Perez-Moreno, B. M. Gumbiner, and J. Schwarzbauer, E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions. Mol. Biol. Cell 18, 2013-2025 (2007).

    Flotillins in intercellular adhesion - from cellular physiology to human diseases
    S. Bodin, D. Planchon, E. Rios Morris, F. Comunale, and C. Gauthier-Rouviere
    J. Cell Sci. 127, 5139-5147 (15 December 2014)

    Cadherin 6 promotes neural crest cell detachment via F-actin regulation and influences active Rho distribution during epithelial-to-mesenchymal transition
    M. R. Clay, and M. C. Halloran
    Development 141, 2506-2515 (15 June 2014)

    The Hippo-YAP signaling pathway and contact inhibition of growth
    B. M. Gumbiner, and N.-G. Kim
    J. Cell Sci. 127, 709-717 (15 February 2014)

    CLASP2 interacts with p120-catenin and governs microtubule dynamics at adherens junctions
    M. N. Shahbazi, D. Megias, C. Epifano, A. Akhmanova, G. G. Gundersen, E. Fuchs, and M. Perez-Moreno
    JCB 203, 1043-1061 (23 December 2013)

    Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1
    R. Fan, N.-G. Kim, and B. M. Gumbiner
    Proc. Natl. Acad. Sci. USA 110, 2569-2574 (12 February 2013)

    Intersection of Hippo/YAP and Wnt/{beta}-catenin signaling pathways
    W. M. Konsavage, and G. S. Yochum
    Acta Biochim Biophys Sin 45, 71-79 (1 February 2013)

    Early events in cell adhesion and polarity during epithelial-mesenchymal transition
    R. Y.-J. Huang, P. Guilford, and J. P. Thiery
    J. Cell Sci. 125, 4417-4422 (1 October 2012)

    Cadherin-dependent mechanotransduction depends on ligand identity but not affinity
    H. Tabdili, M. Langer, Q. Shi, Y.-C. Poh, N. Wang, and D. Leckband
    J. Cell Sci. 125, 4362-4371 (15 September 2012)

    N-glycosylation alters cadherin-mediated intercellular binding kinetics
    M. D. Langer, H. Guo, N. Shashikanth, J. M. Pierce, and D. E. Leckband
    J. Cell Sci. 125, 2478-2485 (15 May 2012)

    E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components
    N.-G. Kim, E. Koh, X. Chen, and B. M. Gumbiner
    Proc. Natl. Acad. Sci. USA 108, 11930-11935 (19 July 2011)

    Role for E-Cadherin as an Inhibitory Receptor on Epidermal {gamma}{delta} T Cells
    Y. Uchida, K. Kawai, A. Ibusuki, and T. Kanekura
    J. Immunol. 186, 6945-6954 (15 June 2011)

    p120 catenin is required for normal renal tubulogenesis and glomerulogenesis
    D. K. Marciano, P. R. Brakeman, C.-Z. Lee, N. Spivak, D. J. Eastburn, D. M. Bryant, G. M. Beaudoin, I. Hofmann, K. E. Mostov, L. F. Reichardt et al.
    Development 138, 2099-2109 (15 May 2011)

    Activation of Formyl Peptide Receptor-1 Enhances Restitution of Human Retinal Pigment Epithelial Cell Monolayer under Electric Fields
    X.-G. Zhang, Y.-N. Hui, X.-F. Huang, H.-J. Du, J. Zhou, and J.-X. Ma
    IOVS 52, 3160-3165 (1 May 2011)

    N-cadherin-mediated cell adhesion restricts cell proliferation in the dorsal neural tube
    K. Chalasani, and R. M. Brewster
    Mol. Biol. Cell 22, 1505-1515 (1 May 2011)

    Tetraspanin CD151 as a target for antibody-based cancer immunotherapy
    J.-F. Haeuw, L. Goetsch, C. Bailly, and N. Corvaia
    Biochm. Soc. Trans. 39, 553-558 (1 April 2011)

    Assembly of Connexin43 into Gap Junctions Is Regulated Differentially by E-Cadherin and N-Cadherin in Rat Liver Epithelial Cells
    R. Govindarajan, S. Chakraborty, K. E. Johnson, M. M. Falk, M. J. Wheelock, K. R. Johnson, and P. P. Mehta
    Mol. Biol. Cell 21, 4089-4107 (1 December 2010)

    PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity
    C. C. Zhang, Z. Yan, Q. Zhang, K. Kuszpit, K. Zasadny, M. Qiu, C. L. Painter, A. Wong, E. Kraynov, M. E. Arango et al.
    Clin. Cancer Res. 16, 5177-5188 (1 November 2010)

    The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth
    C. Dietrich, and B. Kaina
    Carcinogenesis 31, 1319-1328 (1 August 2010)

    Kruppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression
    J. L. Yori, E. Johnson, G. Zhou, M. K. Jain, and R. A. Keri
    J Biol Chem 285, 16854-16863 (28 May 2010)

    Cadherins and Pak1 Control Contact Inhibition of Proliferation by Pak1-{beta}PIX-GIT Complex-Dependent Regulation of Cell-Matrix Signaling
    F. Liu, L. Jia, A.-M. Thompson-Baine, J. M. Puglise, M. B. A. ter Beest, and M. M. P. Zegers
    Mol. Cell. Biol. 30, 1971-1983 (15 April 2010)

    Interplay of Cadherin-Mediated Cell Adhesion and Canonical Wnt Signaling
    J. Heuberger, and W. Birchmeier
    Cold Spring Harb. Perspect. Biol. 2, a002915-a002915 (1 February 2010)

    Adhesive and Signaling Functions of Cadherins and Catenins in Vertebrate Development
    E. Stepniak, G. L. Radice, and V. Vasioukhin
    Cold Spring Harb. Perspect. Biol. 1, a002949-a002949 (1 November 2009)

    Differential regulation of E-cadherin and {alpha}-smooth muscle actin by BMP 7 in human renal proximal tubule epithelial cells and its implication in renal fibrosis
    M. Veerasamy, T. Q. Nguyen, R. Motazed, A. L. Pearson, R. Goldschmeding, and M. E. C. Dockrell
    Am. J. Physiol. Renal Physiol. 297, F1238-F1248 (1 November 2009)

    Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity
    P. D. McCrea, D. Gu, and M. S. Balda
    Cold Spring Harb. Perspect. Biol. 1, a002923-a002923 (1 October 2009)

    Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3
    R. Arulanandam, A. Vultur, J. Cao, E. Carefoot, B. E. Elliott, P. F. Truesdell, L. Larue, H. Feracci, and L. Raptis
    Mol Cancer Res 7, 1310-1327 (1 August 2009)

    Tunable interplay between epidermal growth factor and cell-cell contact governs the spatial dynamics of epithelial growth
    J.-H. Kim, K. Kushiro, N. A. Graham, and A. R. Asthagiri
    Proc. Natl. Acad. Sci. USA 106, 11149-11153 (7 July 2009)

    Anthrax infection inhibits the AKT signaling involved in the E-cadherin-mediated adhesion of lung epithelial cells
    T. Popova, V. Espina, C. Bailey, L. Liotta, E. Petricoin, and S. Popov
    FEMS Immunol Med Microbiol 56, 129-142 (1 July 2009)

    Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis
    S. Getsios, C. L. Simpson, S.-i. Kojima, R. Harmon, L. J. Sheu, R. L. Dusek, M. Cornwell, and K. J. Green
    JCB 185, 1243-1258 (29 June 2009)

    E-Cadherin Regulates Neural Stem Cell Self-Renewal
    P. Karpowicz, S. Willaime-Morawek, L. Balenci, B. DeVeale, T. Inoue, and D. van der Kooy
    J. Neurosci. 29, 3885-3896 (25 March 2009)

    An essential role for p120-catenin in Src- and Rac1-mediated anchorage-independent cell growth
    M. R. Dohn, M. V. Brown, and A. B. Reynolds
    JCB 184, 437-450 (9 February 2009)

    Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis
    C. C. Milsom, J. L. Yu, N. Mackman, J. Micallef, G. M. Anderson, A. Guha, and J. W. Rak
    Cancer Res. 68, 10068-10076 (15 December 2008)

    p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression
    E. Soto, M. Yanagisawa, L. A. Marlow, J. A. Copland, E. A. Perez, and P. Z. Anastasiadis
    JCB 183, 737-749 (18 November 2008)

    Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines
    M. S. Pino, M. Balsamo, F. Di Modugno, M. Mottolese, M. Alessio, E. Melucci, M. Milella, D. J. McConkey, U. Philippar, F. B. Gertler et al.
    Clin. Cancer Res. 14, 4943-4950 (1 August 2008)

    Cadherin switching
    M. J. Wheelock, Y. Shintani, M. Maeda, Y. Fukumoto, and K. R. Johnson
    J. Cell Sci. 121, 727-735 (15 March 2008)

    Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882